The purpose of the present study was to examine the effects of hypoxia at simulated altitudes of FiO₂ 15.4% (8000’ equivalent), FiO₂ 13.2% (12,000’ equivalent), and a Ramp Hypoxic exposure on perceived workload, cardiovascular activity, electrodermal activity, oximetry, and flight simulator performance. A total of 17 participants (10 female & 7 males;​ mean ± SEM, age 24.82±1.6 yrs, BMI 25.87±1.0 who were apparently healthy, asymptomatic, and physically active performed 3 flight tasks using a video game head-mounted display (HMD) flight simulator while exposed to simulated altitudes of Normoxia, FiO₂ 15.4%, FiO₂ 13.2% and a Ramp Hypoxic Exposure (breathing at 8,000 ft altitude for 5 minutes before being exposed to 12,000 ft altitude during the flight simulation) in randomized single-blinded order. Physiological measures and questionnaires were collected to monitor vagal state throughout each simulated altitude condition. The results indicated that acute hypoxic exposure decreased (p≤0.05) in time- and frequency-domain measures of heart rate variability (HRV). Acute hypoxic exposure decreased (p≤0.05) Peripheral Oxygen Saturation (SpO₂), which indicated a significant (p≤0.05) decrease in oxy-gen availability during each hypoxic exposure. Simulated flight tasks showed a decrease in Electrodermal Activity (EDA) skin conductance which indicated reduced hand sweat during the Course and Landing Tasks compared to the Math Task. Analysis of neuromuscular activity using electromyographic (EMG) techniques showed an increase (p≤0.05) in motor unit activation (EMG RMS) and an increase (p≤0.05) in motor unit action potential conduction velocity (EMG MPF) during the Course Task. These results raised the possibility of increased neck strain during particular flying activities, which may occur regardless of exposure to hypoxia. Although, flight performance was not altered during hypoxic exposures, the scores of the symptom questionnaires indicated a greater incidence of hypoxic and simulator sickness during the Math Task. When compared to the other simulated Flight Tasks, the Math Task was found to have the highest workload, with subscores of mental and temporal demand having the lowest performance ratings. This study demonstrates the complex interplay among simulated altitude exposures, physiological responses, and cognitive performance during flight tasks. The stability observed in flight performance at mild hypoxic exposures suggested that potential performance impairments may manifest more prominently under severe hypoxic conditions. The cardiovascular stability noted in this study may be attributed to an effective baroreflex reset in response to hypoxia, underscoring the adaptive nature of the autonomic nervous system. If true, this may represent the adaptive nature of the autonomic nervous system. Moreover, the study highlights the ergonomic implications of using technologies HMD’s in flight simulators, as prolonged use has been associated with neck pain and fatigue. In summary, simulated altitude exposures and their impact on the physiological responses, cognitive performance, and pilot well-being provides valuable insights into the effects of low-level hypoxic exposure on these variables. This study contributes new information on the effects of hypoxia's influence on human performance in aviation, paving the way for more targeted and comprehensive investigations in the future to enhance safety and optimize pilot well-being.